WO2014032676A1 - A solid oral formulation for treatment and/or prevention of overweight and/or for stabilizing blood sugar levels in an individual. - Google Patents

Abstract

The present invention relates to a solid oral formulation comprising an alginate for the treatment or prevention of overweight or obesity, and/or for stabilizing blood sugar levels in an individual, wherein the solid oral formulation is administered together with an aqueous liquid of 350 ml or more, said amount of alginate in the solid oral formulation being sufficient for a gel to be formed having a gel strength of 1000 Pa or more when dissolved or swelled in the aqueous liquid at simulated gastric conditions of pH 3.

Description

A solid oral formulation for treatment and/or prevention of overweight and/or for stabilizing blood sugar levels in an individual . The present invention relates to a solid oral formulation comprising an alginate for the treatment and/or prevention of overweight for both therapeutic and non-therapeutic purposes. The present invention also relates to the use of said formulation for stabilizing blood sugar levels in an individual.

The number of people affected by overweight and obesity continues to rise along with the prevalence of comorbid diseases that result from this condition.

The effective treatment of obesity, however, remains a largely unachieved goal. Many studies indicate that the main causes of obesity are bad nutrition and lack of physical activity. Therefore, in order to prevent obesity it is necessary for people both to change there eating behaviors, affecting a desired change in body weight, and include physical activity in their lifestyles.

In order to induce a weight loss in relation to the diet plan, the main object is to reduce the caloric intake on a daily basis, however in order for an individual to be able to follow a diet, it is important that the individual does not feel hunger nor the complications normally associated with hunger, e.g. faintness. In this respect, foods containing strong- gelling fibers may provide a safe and efficacious strategy for reducing food and thereby caloric intake by stimulating endogenous satiety signaling and/or by stabilizing blood sugar levels. Presently, one of the most promising fibers for this purpose is alginate. Alginate is a non-digestible polysaccharide and can as such be classified as dietary fibre. Dietary fibre has a range of positive physiological benefits and studies have shown that dietary alginate exhibits many of these. There is an improvement in GI barrier function and a reduction in the damaging potential of the luminal contents with changes in the colonic microflora. Dietary alginate reduces intestinal nutrient absorption and promotes satiety both of which have implications for the control of Type II diabetes and obesity. (Brownlee et al., 2005 I. A. Brownlee, A. Allen, J. P. Pearson, P.W. Dettmar, M.E. Havler and M.R. Atherton et al., Alginate as a source of dietary fiber, Critical Reviews in Food Science and Nutrition 45 (6) (2005), pp. 497-510. View Record in Scopus / Cited By in Scopus (28) .

Dietary fibres are grouped into 2 types: soluble and insoluble fibres. The insoluble dietary fibres are present in coarse bread and starchy vegetables. Examples of insoluble fibres comprise cellulose, hemicellulose, lignin and pectin. The soluble fibres are present in fruit and vegetables. Examples of soluble fibres comprise guar, dextran, alginate, starch, amylose, pectin, amylopectin, xanthan, pullulan, carrageenan and gellan. Attempts to use soluble fibres in the production of drinkable products for the control of food intake are disclosed in various patent applications. Thus, WO2008/098579 discloses a diet product comprising an alginate in an aqueous dissolved or swelled form at a pH not causing the alginate to gel. Preferably, the type of alginate is of a low molecular weight having a molecular weight of 150.000 or less. When the pH of the diet product is decreased to around 2, the viscosity may be increased 50 times or more, resulting in a high viscosity gel. WO 2008/022857 discloses a shelf-stable liquid composition comprising a mixture of alginate, HM pectin and water. According to the description, upon ingestion, the liquid composition enhances, the feeling of satiety and/or induces satiation upon ingestion. According to the prior art, such beverages may be effective for the treatment of overweight or obesity. The vast amount of water included in the known beverages may increase the price of the product due to higher transportation and storage costs. Furthermore, consumers, following a diet including the prior art liquid compositions, need regularly to carry heavy bags from the shop to their homes.

To overcome the above-mentioned problems a solid oral formulation is suggested as an alternative. Furthermore, it is believed that consumer compliance is increased because patients not only are used to being treated with capsules, tablets or other solid oral formulations when ill or following a dietary plan, but also because consumption of a solid formulation is much easier to incorporate into a full working day or take before a meal at a restaurant, instead of having to consume larger quantities of a meal substitute.

WO 2003/086360 relates to an oral solid formulation for the production of satiety and for weight loss. The product consists of a dried, porous gel or foam of e.g. an aluminum alginate, i.e. a previously produced gel or foam has been dried, and it is said gel, which is being re-hydrated in the stomach. The above-mentioned patent application does not include clinical tests, but it is asserted that the product, when orally ingested results in a prolonged gastric emptying time and an increased feeling of satiety. The solid formulation in WO 03/086360 is not capable of dissolving at the pH-value in the stomach and said gel will therefore only work as a sponge. A solid oral formulation with similar properties is known from WO 2004/056343. The present inventors have however discovered that a simple swelling of the oral formulation provides an inadequate feeling of satiety, and that addition of certain ingredients is necessary to obtain a better formulation comprising an alginate, when a solid oral formulation is wanted for the treatment of obesity or overweight, and/or for reducing oscillation of the blood sugar levels, including the metabolic syndrome . In this respect it is not only important that a sufficient amount of an aqueous liquid is present in order to allow for an adequate amount of gel to be formed in order to obtain a feeling of satiety, but also that the gel has a sufficient volume and strength in order to be present in the stomach for a sufficient period of time as the gel formed otherwise will be degraded to fast to ensure a prolonged feeling of satiety.

In this respect the inventors have surprisingly found that in order to obtain a large gel strength as well as a sufficient volume, it is important that the formulation comprises a disintegration agent, ensuring that the solid form breaks up when it comes into contact with aqueous fluid, in order to obtain acceptable dissolution rates of the alginates in the formulation. Availability of the alginate in the solid formulation depends on the formulations ability to disintegrate fast enough in the relevant dissolution media. If said disintergration is not present an undesirable effect is found not only on the rate of gel formation but also the degree of alginates turning into a gel, accordingly affecting both the gel strength and stability. As an example can be mentioned, that if no disintegration agent is present it is likely that the solid formulation only becomes wetted on the outside, as the individual alginate particles on the surface to undergo surface swelling and stick to each other, thereby resisting penetration of water into the solid formulation. Disintegrating agents are thus added to the solid formulation for according to the invention to promote the disintegration of the formulation into smaller fragments in an acidic aqueous environment and, thereby increase the available surface area and thus promote a more rapid exposure of the alginate to the content of the stomach. The disintegrating agents can be categorized in three different mechanisms of action: wicking, swelling and deformation. Effective disintegrating agents that do not swell are believed to impart their disintegrating action through porosity and capillary action, also called wicking. Tablet porosity provides pathways for the penetration of fluid into the tablets. Disintegrating particles with low cohesiveness and compressibility act to enhance porosity and provide these pathways into the tablet. Liquid is drawn up or "wicked" into these pathways through capillary action and rupture the inter- particulate bonds causing the tablet to break apart. Materials suitable for acting as wicking agents may be, but are not limited to, colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, alumina, niacinamide, sodium lauryl sulfate, low molecular weight polyvinyl pyrrolidone, m- pyrol, bentonite, magnesium aluminum silicate, polyester, polyethylene, and microcrystalline cellulose.

Swelling is believed to be a mechanism in which certain disintegrating agents such as starch impart their disintegrating effect. By swelling in contact with water or aqueous environment, the adhesiveness of other ingredients in a tablet is overcome causing the tablet to fall apart. Examples of swelling agents may be pregelatinized starch or any type of modified starch, and sodium carboxy methylcellulose.

Deformation is generally thought to be an "elastic" phenomenon where particles deformed under pressure will return to their original shape when the pressure is removed. However, with the compression forces involved in tableting, these particles are believed to be deformed more permanently and are said to be "energy rich" with this energy being released upon exposure to an aqueous liquid.

In a certain aspect of the invention the disintegrating agent is an alkaline salt. Specific examples include NaHC0₃, Na₂C0₃, KHC0₃, K₂C0₃, and any combinations thereof. In other aspects of the invention it is not desired to use substantial amounts of compounds as disintegrating agents, which generate gaseous carbon dioxide when contacted with the gastric conditions. The gaseous carbon dioxide tends to be encapsulated in the alginate gel in the stomach, resulting in a floating raft rather than a preload. In this latter aspect of the invention the amount of disintegrating alkaline salt, such as sodium bicarbonate, is present in an amount of 5% by weight or less, based on the weight of the alginate.

In one embodiment the disintegrating agent is a combination of one or more of the wicking agents, swelling agents and alkaline salts .

The objectives behind adding a disintegrating agent are to increase surface area of the tablet fragments and to overcome cohesive forces that keep particles together in a tablet. Thus, the solid formulation according to the invention will not only lead to increased viscosity of stomach contents inducing a feeling of satiety but will also increase the time period the gel remains in the stomach.

In line with the above mentioned, a solid oral formulation comprising an alginate for the treatment of or prevention of overweight or obesity has been provided, having an alginate amount which is sufficient for the formation of a gel having a gel strength of 1000 Pa or more, when dissolved or swelled in an aqueous liquid at simulated gastric conditions at a pH of 3 or less.

The obtained solid formulation will disintegrate in the stomach where the content of the formulation will be converted into a thick gel whereby the consumer will experience a feeling of satiety. Furthermore, it is likely that the gel formed has an active function in detaining fats, thereby inhibiting their uptake in the stomach or bowels. By these means some food constituents, incl . fats, can pass undigested. Passage through the stomach and bowels is thereby regulated by the formulation as a prolonged time of passage of consumed foods is observed after intake of the solid formulation. Any alginate in any amount may be used in the present invention provided it forms a gel at a pH of 3 or less, said gel having a gel strength of 1000 Pa or more. It is however preferred that a gel strength is higher e.g. 2000 Pa, 4000 Pa, 8000 Pa or more as the gel formed in the stomach otherwise can be degraded to fast to ensure a prolonged feeling of satiety.

The formation of alginate gels can either be obtained due to the presence of multivalent cations in the formulation e.g. in the form of calcium (ionic gelation) or alternatively be obtained when the pH is less than 3.5 (acid gelation) . It is however preferred to use an alginate which undergoes ionic gelation as the inventors has found that it will be possible to use lower concentrations/amounts of alginates in the solid formulation according to the invention.

According to this invention, alginates of any molecular weight may be used for the preparation of the solid oral formulation. In some embodiments of the invention in order to obtain a fast dissemination or dissolution of the solid oral formulation without the use of disintegrating agents, the molecular weight of the alginate should not be above 150,000 Da. However, in order to provide a sufficient effect on satiety, the molecular weight of the alginate should be at least 10, 000 Da. In other embodiments of the present invention it is preferred to use a molecular weight of the alginate, which is 200,000 Da, or above, such as 350,000 Da or above. Alginates of this molecular weight tend to be less soluble; therefore a smaller quantity is generally needed to obtain the same gel strength as obtained with an alginate of lower molecular weight. The inventors have however surprisingly found that if the formulation also comprises a suspending agent it is possible to obtain a very good solubility using alginates having a high molecular weight, i.e. weights above 150 kDa. Within the context of the present invention the tern "suspending agent" means any agent capable of providing the desired solubility and/or dispersion of the alginate in the formulation. Without being bound by theory it is believed that the suspending agent ensures that the alginate particles are diluted and separated by keeping the alginate particles apart, as they are wetted. The ratio of the alginate to the suspending agent is preferably about 1:1 to 20:1, more preferably 5:1 to 10:1, as the inventors have shown said ratios to provides the highest solubility . A preferred suspending agent is selected from the group consisting of inulin, polydextrose , dextrin, oligofructose, and combinations thereof.

Alginates are polysaccharides that provide the main structural component of brown algae (seaweeds) . Alginates are linear copolymers of (1 4) linked β-d-mannuronic acid (M) and GC-1- guluronic acid (G) . The distribution of M and G in alginate chains gives rise to three different block types, namely blocks of poly-M, blocks of poly-G and alternating MG blocks. The chemical composition of alginate is variable according to the seaweed species, within different parts of the same plant (stem or leaf), seasonal changes and the conditions of the sea.

The guluronic segments can associate with the calcium ions to form aggregates similar to an "egg-box" . Within these junction zones the alginate chains are in a regular pleated structure, which is stabilized by multivalent cations, each neutralizing a negative charge on two different chains. As a result, alginates richer in these blocks form stronger gels. The affinity for cations and the gel forming properties of the alginate are mostly related to the content of G residues as when two G residues are adjacent in the polymer they form a binding site for polyvalent cations. In one embodiment the alginate has a ratio of mannuronic acid to guluronic acid (M/G) of less than 1, suitably as low as 0.8 or less. Preferably the amount of guluronic acid is above 60% and the amount of mannuronic acid is below 40% of the total content. Since only guluronic acid is regarded as being responsive to calcium gelation it is preferred to use an alginate having a high guluronic acid content. In accordance with a particular preferred embodiment of the present invention, the alginate used in the present invention is provided in a form in which less than 80%, such as less than 60%, preferable less than 40% and most preferred less than 20% of the total amount of guluronate and mannuronate units are estrified with an alcohol group such as an methyl, ethyl, propyl, hydroxypropyl , hydroxypropylmethyl , propylene glycol group. Particularly, it is preferred that the alginate does not contain any esterified mannuronate or gulluronate groups .

As suitable alginates of this type can be mentioned Satialgine XPU-LVG500 (Algogel DPG JO) obtainable from Cargill (Minneapolis, MN, USA), however a preferred alginate is Manugel® DMB obtainable from FMC Biopolymer as said alginate form a strong gel in the stomach. Further specific alginates to be considered is Manugel® DMB, Protanal® SF 120 RB and Protanal® GP 5450. In general, the alginate is a sodium alginate, however, other metal salts of alginate can also be used. Examples are potassium alginate, which is widely used in foods as a stabilizer, thickener, and emulsifier. Further metal alginates include calcium alginate, magnesium alginate and ammonium alginate.

The inventors have discovered that in a preferred embodiment the alginate in the solid composition is a combination of alginates, preferably a composition comprises at least one low viscosity alginate having a viscosity of less than about 100 mPaS in a 1 wt% aqueous solution and at least one high viscosity alginate having a viscosity of more than about 100 mPaS in a 1 wt% aqueous solution.

As used herein "low or high viscosity alginates" means those alginates having a viscosity lower or higher, respectively, than about 100 mPaS in a 1 wt% aqueous solution when determined on a Brookfield viscometer model LV using spindle No 2 at 60 rpm at 20°C.

Examples of low or high viscosity alginates and preferred alginate combinations comprising high and low alginates are disclosed in the applicants international application no. WO2012/163366 Al .

However, one preferred combination of alginates is about 1.45 g Manugel® GMB; about 1.45 g Manugel® GHB, about 1,5 g Protanal® GP1740, about 0.25 g Protanal® LF 5/60, and about 0.5 g Protanal® GP5450.

A different combination of alginates, which is also disclosed in WO2012/163366 Al is about 0,48 g Manugel® GMB; about 1 g Protanal® GP1740, and about 0,1 g Protanal® GP5450. Said combinations have proven to be especially beneficial for being dissolved in liquid, which is also beneficial when the solid formula is to be dissolved in the stomach. It will be evident for a person skilled in the art, that different amounts of the preferred combinations of alginates can be used, preferably the above mutual ratios.

Any kind of multivalent cation source can be used in the present invention, however a preferred source of multivalent cations is a calcium salt. Said salt is preferably selected from the group consisting of calcium phosphate, calcium carbonate, calcium sulfate, calcium oxide, calcium lactact, calcium citrate, and calcium chloride.

It is however preferred that the used calcium salt has a solubility of at least 5 mg per ml at 20°C and pH 7, ensuring that the calcium ions are available shortly after the solid formulation has been disintegrated in the stomach. All known alginate preparations in the art rely on endogenous gastric acid to trigger the solubility of the calcium salt, however since gastric pH is not a consistent factor and varies among individuals, e.g. due to meal consumption, time and medication usage, and compositions which are decomposition-sensitive to pH can be affected accordingly. It is therefore advantageously if the calcium ions are immediate available after the formulation reaches the stomach, and using a calcium salt having a good solubility ensures that the calcium ions does not become the limited factor during geletion. In this respect calcium chloride have proven to be especially useful, as said salt already are accepted for human consummation, however other calcium salt having similar properties are also contemplated within the scope of the invention. When it is desired to design a solid oral formulation in which the gel is reversible, cross-linking polyvalent metal ions are generally provided in an amount of 10% by weight or less, based upon the amount of alginate. When an increase in gastric emptying time is desired, a salt comprising calcium ion may be included to increase the gel strength of the gel formed of the alginate. Examples of salts including an aluminium ion are aluminium carbonate, aluminium chloride, and aluminium hydroxide. In embodiments where cross-linking ions are desired, the amount of salt comprising the cross-linking polyvalent metal ions is typically, 15% by weight, preferably 25% by weight of the alginate in a unit dosage form.

It is preferred that the solid oral formulation according to the invention does not comprise any additional active pharmaceutical ingredients.

Surprisingly, the present inventors have found that satiety- inducing factors are strongly correlated with the volume of a solid product containing soluble dietary fibers and the gel strength thereof. Thus, it has been found that the effect of a solid product according to the invention administered with a volume of 330 mL was not significant, when compared to the administration of 330 mL of placebo, whereas when the solid formulation was administered with an increased volume the feeling of satiety was increased significantly which subsequently lead to a reduction in prospective food intake.

It is furthermore preferred that the gel at simulated gastric conditions of pH 3 has a volume between 400 ml and 600 ml, preferably about 500 ml as said volume has proven to be especially relevant in order to obtain the desired satiety effects .

In a preferred embodiment the solid formulation according to the present invention is taken in combination with a sufficient amount of aqueous liquid, preferably in an amount of 350ml or more. The aqueous liquid is ingested together with the oral solid formulation or preferably with 30 minutes after the administering of the solid oral formulation. In other embodiments the amount of aqueous liquid may be increased so that the volume may be 400 mL, 450 mL, 500 mL, 550 mL, 600 mL, or more. In another aspect, the present invention relates to a solid oral formulation mentioned above and the use thereof for increasing the perceived satiety. In still another aspect of the invention, it relates to the solid oral formulation mentioned above and the use thereof for decreasing the prospective food intake.

Even though it is desirable to obtain a specific volume of the gel in the stomach it is also relevant to obtain sufficient gel strength, as the gel formed in the stomach otherwise will be degraded to fast to ensure a prolonged feeling of satiety. In this respect it is desirable that the gel weight obtained after the pH value is lowered from pH 7 to pH 2, is above 90 g/100 ml water, more preferably above 93 g/100 ml water and even more preferably above 95 g/100 ml water, as an increase in gel weight is beneficial also this has proven not only to be beneficial in relation to a feeling of satiety but will also slow gastric emptying, stimulate gastric stretch receptors and reduce intestinal nutrient uptake and influence the glycaemic response .

However, the inventors have surprisingly found that by raising the concentration of multivalent cations available during gelation it is possible to lower the concentration of the alginates in the solid formulation and still obtain the same or equivalent gel strength, volume and weights as obtained using higher alginate concentrations.

The solid oral formulation of the present invention may be administered as a single unit dosage or multiple dosages, i.e. 2, 3, 4 or more unit dosages. As an example can be mentioned that if the formulation according to the invention is intended for providing a stabilized blood sugar level, then three daily dosages is contemplated.

Each unit dosage may comprise a concentration of the alginate adjusted to meet the result desired. As an example can be mentioned that each dosage may comprise at least 200 mg alginate, preferably at least 500 mg or at least 800 mg, preferably at least 1200 mg. Each dosage may comprise up to 5 g alginate, preferably around 3 g.

The subject receiving the product in question in terms of unit dosage (s) is generally an adult. If an adolescent or a child is treated the number of unit dosages may be adjusted to the age of the person being treated.

The solid oral formulation prepared using the alginates mentioned above may be described in terms of the viscosity and/or the tensile modulus of their respective physical state after having been exposed to conditions simulating the gastric conditions, such as aqueous conditions at a pH of 2 or less. The viscosity may readily be measured using any conventional equipment, for example using a rheometer of the Bohlin product range of Malvern Instruments Ltd. (Malvern, Worcestershire, UK) such as a Bohlin CVOR rheometer.

The gel strength can be measured as Young's (tensile) Modulus following the formula:

_ tensile stress σ F/A_® FLQ

tensile strain ε AL/LQ AQAL where

E is the Young's modulus (modulus of elasticity)

F is the force applied to the gel;

A₀ is the original cross-sectional area through which the force is applied; AL is the amount by which the length of the gel changes;

L₀ is the original length of the object.

When the alginate used in the present invention is exposed to a pH of 3 or less, e.g. as found in gastric juice (around 1.5 at fasting conditions), it forms a gel. The formation of the gel may be observed with a corresponding increase in viscosity. Thus, when exposed to acidic conditions at a pH of 3 or less, the solid oral formulation containing the alginate will swell or dissolve and obtain a certain viscosity. The gel formed upon lowering the pH will generally be of non-Newtonian rheology. For example, the gel may be characterised as being of pseudo- plastic rheology meaning that the observed viscosity of the gel is decreased when the gel is exposed to an increasing shear rate. The viscosity of the gel will typically be recorded at ambient temperature at shear rates between 0.1 s ¹ and 90 s ¹ , e.g. the viscosity of the gel may be measured at 20 s ¹ and the recorded viscosity may be compared to the viscosity of the aqueous liquid before formation of the gel.

Preferably, the solid oral formulation as described in the present invention, when dissolved or swelled in an aqueous liquid to be consumed together with the oral formulation, when measured at a shear rate of 0.1 s ¹, pH 3, has a viscosity of 7 pas or more.

The solid oral formulation may also be described in terms of its water retention capacity upon the formation of a gel. The formation of a gel will result in binding of water molecules within the gel, and in one embodiment the obtained gel has a water retention capacity (WRC) of at least 13 g of water per gram of the formulation. It is believed that this WRC may be indicative of the satiety inducing effect of the gel, i.e. of the formulation. In particular, the higher the WRC is of an alginate the better the satiety effect is of the formulation. The WRC of the formulation may be determined by the formation of a gel by lowering the pH and determining the mass of the gel and the mass of the free water, and from these parameters enable a calculation on how much water has been retained in the gel. For example, the WRC may be measured by centrifugation of the gel and recording the weight of the gel and the weight of the supernatant; appropriate conditions may be centrifugation for 10 min at 3500 rpm (e.g. in a Rotina 48R centrifuge from Hettich Zentrifuge) . The gel formation caused by the alginate in the oral formulation may also be reversible, when no or only a small amount of cross-linking metal ions, such as calcium ions, are used. Thus, in this embodiment the formation of the gel by lowering the pH to 3 or less may be reversed by increasing the pH to above 3, suitably above pH 5. The present inventors believe that a reversible formation of a gel is advantageous for certain products which increase satiety. Upon oral intake the solid formulation together with any liquid in the stomach, will be exposed to the low pH found in the stomach which will trigger the formation of a bulking gel, which subsequently will increase the feeling of satiety. However, when the gel leaves the stomach it will be exposed to increasing pH in the duodenum (pH 6-8) which will reverse the gel formation. Thus, the effect of the gel will be limited to the stomach and any adverse effects such as constipation due to the bulking agent may not occur or only occur to a limited extent.

The solid oral formulation of the present invention may contain further biopolymers. Examples of such biopolymers include pectin, cellulose, xanthan, curdlan, pullulan, hyaluronic acid, gelatin, chitin, inulin, carrageenan, xanthan gym, dextran, etc. In a certain embodiment of the present invention the alginate is used in combination with pectin. Pectins are a common type of carbohydrate gelling agents, generally obtained from dilute acid extracts of citrus or apple pulp. They are an important constituent of the cell walls and soft tissue of vegetables and fruits, where they contribute to the mechanical properties of the cell wall and influence cell adhesion. For example, pectins are found in root crops such as carrots and beetroot, as well as in tubers, such as potatoes; and are commercially extracted from citrus peels, apple pomace and sugar beet pulp. Pectin is composed of long, regular sequences of 1, 4-linked-D-galacturonate residues which in nature may be partially methyl-esterified . A typical pectin molecule comprises of 200 to 1000 galacturonic acid units connected in a linear chain having alternating rhamnose units inserted into the main uronide chain. The ester content varies with the source of the raw material and may also be varied during extraction. Pectins are divided into two main categories: high methoxylated pectins (hereafter referred to as HM pectin) , which are characterized by a degree of methoxylation above 50%, more particularly between 50% and 80%, and low methoxylated pectin (hereafter referred to as LM pectin) having a degree of methoxylation below 50%, more particularly between 30% and 50%. As used herein, "degree of methoxylation" is intended to mean the extent to which free carboxylic acid groups contained in the polygalacturonic acid chain are present as the methyl ester. Both HM and LM pectins form gels. However, these gels are formed via totally different mechanisms (Voragen et al, In Food polysaccharides and their applications, pp 287-339. Marcel Dekker, Inc. New York, 1995) . LM pectin forms a gel in the presence of calcium; thus, it is "calcium-reactive." The calcium-LM pectin gel network is built by formation of what is commonly referred to as an "egg-box" junction zone in which Ca²⁺ causes the cross-linking of two stretches of polygalacturonic acid chains. Calcium-LM pectin gel formation is influenced by several factors, including DM, ionic strength, pH, and molecular weight. Furthermore, the calcium-LM pectin gelation is more efficient at a neutral pH of about 7.0 than at an acidic pH of about 3.5. Lastly, the addition of a monovalent counter ion (NaCl) enhances the gelation, i.e., less calcium is required for gel formation. HM pectin forms a gel in the presence of high concentrations of co-solutes, such as sucrose, at low pH . HM pectins are generally not reactive with calcium ions and therefore cannot form a calcium gel. However, certain HM pectins have been reported to be calcium sensitive and capable of calcium gel formation. In addition, HM pectins can be made calcium-reactive by a block wise de-esterification process while still having a DM of >50%. See, Christensen et al . U.S. Pat. no. 6, 083, 540. Pectins are typically utilized in the food industry and classified by the FDA as "GRAS" (Generally Regarded As Safe) . Also, they have been used as colloidal and anti-diarrhea agents. Recently, pectins have been utilized in the areas of medical device and drug delivery (Thakur et al . , Critical Reviews in Food Science & Nutrition 37, 47-73, 1997) . In the case of drug delivery, pectin has found its presence in many experimental formulations for oral drug delivery to the colon because bacteria present in this region of the intestines readily degrade pectin.

In an aspect of the present invention, the solid formulatin according to the present invention comprises 0.05-5.0 wt% HM pectins, which are preferably characterized by a degree of methoxylation of above 50%, preferably within the range of 50- 90%, still more preferably within the range of 55-85% most preferably within the range of 60-80%.

According to WO 2008/022857 it was found that the molecular weight of the pectin does not affect the gel strength of the gel formed upon ingestion, but does affect the viscosity of the liquid composition itself. More in particular, it was found that low molecular weight HM pectins form similarly strong interactions with alginate, as do high molecular weight HM pectins. Thus, the addition of low molecular weight HM pectin will reduce the viscosity of the product and improve the mouth feel thereof, without a concomitant decrease in strength of the gel particles formed in the stomach as compared with the use of high molecular weight HM pectins. Therefore, according to a preferred embodiment, solid formulations are provided, wherein the average molecular weight of the HM pectin is within the range of 50-500 kDa, more preferably within the range of 75-250 kDa, still more preferably 90-200 kDa.

In the above aspect of the invention HM pectins are used in combination with alginates, since they are capable of forming a sufficiently rigid matrix at the pH found in the stomach of a normal human, typically a pH of 3 or less. The solid oral formulation according to the invention typically contains 0.08 - 2.5 wt . %, preferably 0.1 - 1.0 wt . %, more preferably 0.2 - 0.8 wt . % of HM pectin based on the total weight of the composition.

The oral formulation prepared by using an alginate is not particularly limited to the amount of the alginate, as long as the gel formed has gel strength of 1000 Pa or more at simulated gastric conditions of pH 3 or less. A skilled person may easily determine the amount of alginate to be used in a solid oral formulation by using the formula for Young's modulus above. Thus, when the amount of an aqueous liquid and the composition of the oral formulation, including the type of alginate, a simple routine experiment will show whether a gel with a strength of 1000 Pa or more is formed. In one embodiment the amount of alginate in the solid formulation is selected in the range of 0.5 g to 20 g. The solid oral formulation may be present as a single or several unit dosages to make it possible to swallow the formulation.

The oral formulation according to the present invention may comprise one or more pharmaceutical acceptable carriers in addition to the active constituent ( s ) described above. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. In a certain embodiment, the alginate is purified.

It will be appreciated that the amount of the formulation required for treatment or prevention will vary according to the form of administration, the disorder to be treated, the condition, age, the file history of the subject, and the gelenic formulation of the formulation, etc. When treating a subject diagnosed with a certain disease, the amount of active components are preferably present in an amount effective to alleviate the symptoms of the patient.

The solid oral formulation of the present invention may be formulated as tablets, pills, capsules, powders, etc. The solid oral formulation may furthermore contain one or more carriers.

The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the active components are administered. The carriers in the formulation may comprise a binder, such as microcrystalline cellulose, polyvinylpyrrolidone (polyvidone or povidone), gum tragacanth, gelatine, starch, lactose or lactose monohydrate ; a lubricant or surfactant, such as magnesium stearate, or sodium lauryl sulphate; a glidant, such as colloidal silicon dioxide; a sweetening agent, such as sucrose or saccharin; and/or a flavouring agent, such as peppermint, methyl salicylate, or orange flavouring.

The formulation for oral administration, e.g. tablets and pills, may be obtained by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by mixing the constituent ( s ) , and compressing this mixture in a suitable apparatus into tablets having a suitable size. Prior to the mixing, the alginate may be mixed with a binder, a lubricant, an inert diluent and/or a disintegrating agent and the alkaline salt may be mixed with a diluent, a lubricant and/or a surfactant. When one or more carriers are present, the alginate powder may be dry-mixed mixed with a binder, such as microcrystalline cellulose and/or a surfactant, such as sodium lauryl sulphate and/or a disintegrating agent and/or a salt comprising a cross- linking polyvalent metal ion until a homogeneous mixture is obtained. Optional, another binder, such as polyvidone, is transferred to the mixture under stirring. This mixture may be passed through granulating sieves if needed and dried by desiccation before compression into tablets in a standard compressing apparatus. Alternatively, the tablets are prepared without the addition of carriers. According to this alternative embodiment the free-flowing alginate is compressed into tablets optional after mixing with magnesium stearate. Conventional methods for producing a solid form of the pharmaceutical composition may be found in the European Pharmacopoeia, which is included herein by reference.

A tablet may be coated or uncoated. An uncoated tablet may be scored. A coated tablet may be coated with sugar, shellac, film or other enteric coating agents.

In a preferred embodiment the solid oral formulation is in the form of a shell/core capsule wherein the core comprises the formulation according to the invention, preferably in the form of a powder or a viscous paste, and the shell is arranged to quickly dissolve when the capsule reaches the stomach. Such an embodiment will ensure that the alginate particles are easily and quickly dispersed in the stomach, providing a fast gel formation such that a fast and prolonged feeling of satiety is achieved. Both soft and hard capsules are contemplated within the scope of protection.

Shell materials capable of easily dissolving in the stomach are known in the art, however gelatin is used in a preferred embodiment . The effect of the solid oral formulation of the present invention is believed to arise from an increased feeling of satiety (reduced appetite) in the subject to whom the solid oral formulation is administered, so that the subject after having been administered the product will tend to ingest less food (e.g. reduce the spontaneous energy intake) .

The solid formulating according to the invention also provides less oscillation of the blood sugar and hence a stabile feeling of satiety and well being. It is known that stable blood sugar levels have a benefit in e.g. promoting weight loss; controlling hunger and reducing the risk of diabetes. Hence, the alginate, when used for the preparation of the product according to the invention, is suited as a supplement which can reduce the amount of intake during ingestion of a meal and/or provide stabilized blood sugar levels. Thus, in order for the product to have the desired effect a preferred administration is prior to taking in a meal, e.g. as a "preload". In one embodiment, the product is administered no more than 2 hours prior to a subject's intake of a meal. The administration of the product may also occur sooner than 2 hours prior to a meal intake, such as not more than 1 hour prior to a subject's intake of a meal, e.g. not more than 30 minutes prior to a subject's intake of a meal. Administration of the solid oral formulation may be relevant before any meal of the day for the subject, although it may be advantageous to administer the product prior to the meal of the day when the subject typically has the largest energy intake during the day. Ideally the product should be taken before any major meal intake, i.e. ideally three times per day before the three major meals (breakfast, lunch and dinner) . However, the effect of the solid oral formulation on satiety and blood sugar levels may also prevent the subject in consuming food or snacks between meals, which is considered advantageous for a weight loss plan for a subject.

The solid oral formulation may be administered daily for a period with a duration of several days or weeks, for example as a course of a diet. For example, according to one embodiment the solid oral formulation is administered one or more times per day, the interval between administrations being at least 2 hours. Multiple administrations during a day may be especially advantageous in order for a subject to obtain a weight loss. In a preferred embodiment, the solid oral formulation is administered prior to all meals ingested by a subject during a day. In other embodiments, the formaultion is administered before two meals, such as the two meals normally containing the highest energy intake for the subject during a day .

In yet another aspect the invention relates to a method for regulating, e.g. decreasing, appetite in a subject and/or for regulating the blood sugar levels in an individual. This method may e.g. be used in a diet with the intention to cause a weight loss to the subject; for example a subject may desire to loose weight for cosmetic reasons or alternatively the subject may be pathologically obese and be in need of weight loss for medical reasons. A diet dosage regimen will typically have a duration of several days or weeks depending on the aim of the subject undergoing the diet. For example, the subject may intend to loose a certain amount of body mass. The method for regulating appetite may thus comprise the daily intake, such as one to four times a day, preferably prior to a meal, of the formulation according to the invention in order to help the subject to follow the diet. The daily intake may be continued for the duration of the diet. Figure 1 shows the subjective feeling of appetite after intake of a sodium alginate supplement or a placebo based on the results of a Visual Analogue Scale (VAS) questionnaire.

Figure 2 shows the results presented in Figure 1 as incremental Area Under Curve (iAUC) .

Figure 3 shows the results of the VAS questionnaire summed into an appetite score.

Figure 4 shows the energy uptake during an ad libitum meal following intake of low and high dosages of alginate supplement and corresponding placebo supplements, respectively.

Figure 5 shows self-reported estimates of well-being during a study of alginate test supplements or placebo.

Figure 6 shows changes in systolic blood pressure during treatment with low dosage of alginate or placebo.

Figure 7 shows changes in diastolic blood pressure during treatment with high dosage of alginate or placebo.

Figure 8 shows the concentration of paracetamol in the blood after treatment with alginate supplement or placebo in low dosage .

Figure 9 shows the concentration of paracetamol in the blood after treatment with alginate supplement or placebo in high dosage .

Figure 10 shows the measurement of gel strength (elastic modul, Pas) recorded by oscillatory shear rheology of the Manugel® DMB. Figure 11 shows the gel strength (elastic modul, Pas) of Manugel® DMB in relation to the calcium content of the formulation according to the invention. EXAMPLES

The purpose of the below-mentioned experiments was to select an appropriate alginate for use in the preparation of a solid oral preparation. Characterization of alginates is described in Example 1 and 3, and in Example 2 a series of tests were designed to measure the effect of the solid oral formulation in combination with an intake of a volume liquid. 500 mL liquid was compared to an alginate preparation with 330 mL liquid.

Example 1

Selection of an alginate

Methods

Three different alginates were provided by Cargill, Inc. (Minneapolis, MN, USA) and characterised for potential use in a solid oral formulation. The alginates are referred to as Satialgine S20, XPU-LVE500 and XPU-LVG500.

Solutions of the alginates of concentrations of 5, 7.5, 10, 12, 15, 20, 25, 30 and 35 g/L were prepared by initially weighing alginate powders on an analytical balance (Sartorius Analytic A2005, Sartorius, Germany) and then dissolving the alginates in 100 mL aliquots of water (milli-Q water) in glass beakers using magnetic stirring at 500 rpm. After 5 min the beakers were transferred to a water bath at 39°C and the fibers allowed to dissolve for a further 90 to 120 min.

Aliquots of 50 ml volume were withdrawn from each solution and transferred to plastic beakers where 2 mL aliquots of 500 mM HC1 were added at 10 s intervals under magnetic stirring (600 to 800 rpm) until a pH of 1.20 was reached. The pH was monitored using a Metrohm Swiss model 691 pH-meter. Viscosity was measured using a Bohlin C-Vor rheometer (Malvern Instruments Ltd.) . The fibre solution (at pH 5.50 to 6.00) or the gel mass (pH 1.20) was carefully transferred to a steel cup (DG 47/27 double gap, 10 ml or v25, 10 mL, respectively) and left standing for 5 min to equilibrate the sample before recording the viscosity at a constant temperature of 20°C. The measurements were conducted at different shear rates between 0.1 and 90 s ¹ with 15 registrations over a time span of 5 min.

Analysis of oscillatory shear rheology was performed to describe the ability of the viscous gels to resist mechanical stress and thereby characterize the fragility of the network of the gel mass. Oscillatory shear rheology was analyzed on the rheometer at a constant shear frequency of 1 Hz; the stress amplitude was varied over 25 steps where the mechanical stress was controlled and gradually increased from 1 to 500 Pa. Stress was applied for 12 s at a time for each step and the amplitude was registered, and the elastic modulus (C) and the viscous modulus (G'') were calculated.

The water retention capacities (WRC) of the gelled alginate samples were analyzed by centrifuging at 3500 rpm for 10 min in a Rotina 48R centrifuge from Hettich Zentrifuge, Germany and subsequently measuring the weight of the supernatant and the gel. The WRC was expressed in mass of water retained per liter of alginate solution prior to gelation and also in specific values per dry mass of alginate.

Reversibility of the gel formation was examined by transferring the gelled samples to 100 mL disposable plastic beakers with magnetic stirring at 600 to 800 rpm and adding 500 μΐ aliquots of 1 M NaOH every 30 s. The pH was monitored using the Metrohm Swiss model 691 pH-meter. Addition of NaOH was continued until the sample became liquid again. The amount of NaOH added was noted as well as the time for reversion as recorded using a stop watch. Analysis of gel weight, WRC and reversibility was repeated three times and viscosity measurements twice. Results

It was found that gel viscosities increased with increasing alginate concentration for all three alginate types. The XPU-LVG500 alginate provided a viscosity at a shear rate of 20 s¹ of about 5 Pas at a concentration of 15 g/L, and at 25 g/L and above the viscosity was above 10 Pas. In contrast, the XPU-LVE500 alginate did not provide a gel with a viscosity above 5 Pas at any tested concentration, whereas the Satialgine S20 did not provide a gel viscosity above 10 Pas at the tested concentrations .

Table 1 shows the transition points where the viscous modulus (G'') for each of the three alginates surpassed the respective elastic modulus (G'), i.e. where G'=G''. This point illustrates the value of shear stress where the gel changes from an elastic gel to a gel of a more liquid character. A low value indicates a fragile gel whereas a higher value generally indicates a more resilient gel .

Table 1 Transition points (G'=G'') recorded in oscillatory shear rheology

Concentration Satialgine XPU-LVE500 XPU-LVG500

(g/L) S20 (Pa) (Pa)

(Pa)

25 281 57.4 204

30 204 108 530

35 149 78.8 386

At lower concentrations the Satialgine S20 alginate generally had higher values for the transition points than the other alginates. However, at higher concentrations, e.g. at 30 g/L and above the XPU-LVG500 alginate provided a more resilient gel. Provision of a resilient gel upon acidification is seen as advantageous for the product. The XPU-LVG500 alginate was found to provide a higher WRC than the other alginates at all concentrations analysed. However, it was found that the specific WRC values varied with the concentration of alginate in the solution for all three alginates. Solutions of XPU-LVG500 consistently provided a WRC upon gel formation above 20 g/L at all concentrations, and a concentration of only 10 g/L of XPU-LVG500 was required to provide a WRC above 400 g per L alginate solution.

Gel formation for all three alginates was found to be reversible by addition of sodium hydroxide. The amount of sodium hydroxide required for reversal for the alginates XPU-LVG500 and Satialgine S20 did not differ significantly, whereas XPU-LVE500 required less sodium hydroxide. Following reversal of gel formation a higher final pH was recorded for Satialgine S20 than the other two. Gel reversal for XPU-LVE500 generally occurred faster than for XPU-LVG500 and Satialgine S20, but at concentrations above 25 g/L the reversal for XPU-LVG500 was significantly faster than for Satialgine S20; at concentrations above 20 g/L gel formation for XPU-LVG500 was reversed in about 10 min for all concentrations.

On this basis it was estimated that the alginate XPU-LVG500 at a concentration of 30 g/L provided an interesting viscosity after gel formation, resilience of the gel, water retention capacity and reversal time for gel formation. It was therefore decided to conduct experiments with XPU-LVG500 at 30 g/L as described in Example 2. However, this selection should not be regarded as limiting for the invention, and it is contemplated that other alginates may also be used within the scope of the invention or that combinations of different alginates may likewise be employed. Example 2

Ά. Experimental design

A study with 19 healthy males and females in the age of 20 to 45 years was conducted. The subjects were normal to moderately obese (BMI 21-28 kg/m²) .

The experiment was based on a total of four meal experiments. A meal experiment consisted of a standard breakfast meal of 2 MJ and an ad libitum lunch meal. Before each meal a test supplement was administered to the subjects with a pre-load time of half an hour.

The test subjects were randomised into four different treatments by randomised block design. Each treatment being either a specific dosage of alginate or a placebo. Table 2 presents the type, concentration and dosage of the respective fibre under examination. The placebo and respective sodium alginate dosages (both in form of tablets) was tested with simultaneous consumption of either 330 mL water or 500 mL water, such that the final concentration of alginate in the stomach was 30g/l. The alginate containing tables contained NaHC0₃ as a disintegrating agent. The test subjects only performed limited physical activity which was reproduced with each experiment. In addition, the test subjects were restricted from hard exercise within 24 hours prior to each meal experiment. On the evening of the day prior to a meal experiment a standardised evening meal of 4 MJ from Department of Human Nutrition, University of Copenhagen was given. Intake of water, lavatory visits and other activity was noted on the first meal experiment and reproduced on later experiments . Table 2

Test supplement Dose Total amount of

alginate in

tablet (g)

Placebo 330 mL 0

+ 3% alginate XPU- ^■LVG500 330 mL 9.9

+ 3% alginate XPU- ^■LVG500 500 mL 15

Placebo 500 mL 0

In the beginning of each meal experiment the blood pressure of each test subject was measured. A Venflon catheter was put in place to take blood samples during the meal experiment. The subjective feeling of hunger for each test subject was registered on a Visual Analogue Scale (VAS) every half an hour. The VAS test contained four parameters in order to determine an appetite score defined as:

Appetite score = (Satiety + stuffedness + (100 - prospective intake) + (100 - hunger) ) /4

Thus, each test subject reported their subjective feelings for each parameter to calculate the score; the score was expressed in the unit millimeters.

The test supplement was based on sodium alginate fibres (XPU- LVG500) extracted from brown seaweed in a concentration of 3% (equivalent to 15 g of fibre per ½ L of test supplement) . Characterisation of the alginate is described above in Example 1.

B. Effect of alginate supplement on appetite

In the experiment the subjective feeling of appetite was measured using a VAS questionnaire as explained above, and the results of the VAS questionnaire are presented in Figure 1 as a function of time (in min) . The questions regarded hunger, satiety, stuffedness and prospective intake, and Figure la-d show the values obtained for an alginate dosage together with 330 mL water, respectively, and correspondingly Figure le-h show the respective values for an alginate dosage together with 500 mL water.

From the results it is apparent that test subjects experienced a significant increase in satiety and reduced prospective intake when treated with a high dosage of sodium alginate compared with placebo treatment. The corresponding treatment with low dosage of sodium alginate did not show a significant difference in appetite between alginate based supplement and the placebo treatment.

Figure 2 plots the results of Figure 1 as incremental Area under Curve (iAUC); the iAUC is calculated as the area under the curve from 0 min to 270 min for each test supplement, i.e. placebo with 330 and 500 mL water and alginate with 330 and 500 mL water, respectively. Figure 2a shows the iAUC for the 330 mL water and alginate dosages, and Figure 2b shows the iAUC for 500 mL water and alginate dosages. Comparing the rating of appetite as iAUC it is also shown that treatment with high dosage of alginate-based tablets (15 gram) increases the feeling of satiety with approximately 40% (P<0.01) and reduces prospective intake with approximately 50% (P<0.01) . Furthermore, a tendency to decreased hunger with approximately 30% (P=0.07) was found. Treatment with low dosage of alginate- based tablets (9.9 gram) did not show significant difference from the placebo based treatment, however, a non statistical trend in favour of alginate was observed (P>0.1) .

The results of the VAS questionnaire is summed into an appetite score calculated as described above for each of the four test supplements. The appetite scores are presented in Figure 3 as a function of time from 0 to 270 min; Figure 3a shows the appetite scores for the 330 mL water and alginate dosages, and Figure 3b shows the score for 500 mL water and alginate dosages. The experiments showed an increased appetite score of approximately 20% and 60% for low and high alginate-based supplement treatment, respectively, compared with the corresponding placebo treatments. An increased appetite score indicates increased satiety and feeling of fullness together with reduced hunger at prospective intake.

C. Ad libitum energy intake

In the experiment outlined above under A. Experimental design, the spontaneous energy intake during the ad libitum lunch meals was found to be significantly lower with alginate-based treatment at low dosage (9.9 gram) compared with placebo treatment. Table 3 and Figure 4 present the results of the measurements with Figure 4a showing results for alginate unit dosages with 330 mL water and Figure 4b showing results for alginate unit dosages with 500 mL water. The difference was analysed using variance analysis (ANOVA) in a mixed linear model adjusted for significant effect of covariates . The energy uptake was found to be nearly 10% lower when treated with a low dosage of alginate tablets compared to placebo treatment. A lower spontaneous energy intake of 5% was also observed for the high dosage of alginate tablets. From the results it is also found that the high dosage of alginate reduces the energy uptake the most in absolute figures.

Table 3

Alginate Placebo P-value

Energy intake (kJ) at low 3237 ± 184 3513 ± 183 P<0.05 dosage (9.9 g alginate +

330 mL water)

Energy intake (kJ) at high 3121 ± 200 3280 ± 197 P>0.05 dosage (15 g alginate + 500

mL water)

ANOVA : effect of treatment (p<0. D. Side-effects from intake of test supplement

Side-effects were registered during the experiment outlined above under A. Experimental design. Table 4 presents the number of single accounts of self-reported side-effects during intake of alginate-based supplement and placebo supplement. The reported number of side-effects did not differ significantly between alginate containing test supplement and placebo (P>0.1) .

Table 4

Side-effect Alginate+ Placebo+ Alginate+ Placebo+

330 itiL 300 itiL 500 itiL 500 itiL

Heatburn 1 1 3 2

Ructus 2 3 4 2

Distended 5 3 8 7

Nausea 8 3 8 7

Stomach ache 0 1 1 0

Rumbling in 7 9 11 10

the stomach

Wind 8 8 8 8

Diarrhea 0 1 0 2

Constipation 0 0 0 0

Total 31 29 41 36

Figure 5 presents the test subjects' self-reported estimates of well-being with Figure 5a showing the results for alginate unit dosages with 330 mL water and Figure 5b showing results for alginate unit dosages with 500 mL water. Neither side-effects nor measure of well-being indicate any significant difference between treatment with sodium alginate tablet or placebo tablets (P>0.1) . E. Hemodynamic measurements

The systolic and diastolic blood pressure of the subjects of the experiment outlined above under A. Experimental design were measured regularly throughout the experiment. Figure 6 and 7 present the results of the measurements for systolic and diastolic blood pressure, respectively, expressed as changes in baseline corrected blood pressure compared to the value at t=0. The a-panels show the values for the alginate unit dosages with 330 mL water and the b-panels for the alginate unit dosages with 500 mL water. No apparent differences were seen with respect to the systolic blood pressure when comparing the treatments of alginate supplement of high and low dosage with the corresponding placebo supplemental drinks.

The diastolic blood pressure was significantly lowered during the course of the meal experiment when treating with a high dosage of alginate supplement. The low dosage did not show the same tendency. Treatment with high dosage of alginate supplement resulted in a significant reduction of the diastolic blood pressure of -2% compared with placebo results.

F . Stomach clearance rate

Paracetamol was used as marker for the rate of emptying the stomach. Since paracetamol is not absorbed from the stomach but will only reach the blood stream after being absorbed from the duodenum the level of paracetamol in the blood provides an indication of the clearance rate of the stomach. Paracetamol was administered together with the breakfast meal in a total dosage of 1500 mg in 3 tablets of 500 mg each. The concentration of paracetamol in the blood was used as a measure for the rate of emptying the stomach.

Figure 8 and 9 present the levels of paracetamol in the blood of the subjects for the 330 mL+alginate unit dosages and the 500 mL+alginate unit dosages, respectively. The values are displayed as a function of time from 0 to 270 min in the a- panels, and in the b-panels the integrated results of the a- panels are shown as iAUC-plots. The blood levels of paracetamol after administration of alginate dosage or placebo with 330 mL water did not differ significantly, and thus no effect was found on the rate of emptying the stomach. However, after administration of the alginate supplement with the 500 mL dosage the blood level of paracetamol was significantly lower than for the administration of placebo, and a reduced rate of emptying the stomach was thus observed when treating with a high dosage of alginate compared to the corresponding placebo treatment .

Example 3

In order to evaluate if other kinds of alginates also could be considered preferred in the solid oral formulation according to the invention, were Manugel® DMB from FMC-Biopolymers (Philadelphia, USA) evaluated with the with the purposes of examining the gel strength and its dependence of calcium concentration. Similar experiments were conducted using Manugel® LBA and Protanal® LFR 5/60, both provided by FMC Biopolymer (Philadelphia, USA) - however these experiments are not shown.

The alginate was prepared in four different concentrations (0.75 vol%, 1.5 vol%, 2.25 vol% and 3 vol%) and with addition of the insoluble salt of calcium carbonate 0.5 M as an active component for supporting the gel formation (at pH 1.5-2) .

In addition we evaluated the gel strength with varying calcium concentrations, with increased concentration of calcium. 7.5ml 0.5 M calcium carbonate was added for the two lowest alginate solutions and 2.5ml 0.5 M calcium carbonate for the two highest alginate solutions. Methods

Table 5 shows the measurements conducted on Manugel DMB. Table 5

Alginate Added calcium Repetitions of c concentration (5% CaC0₃ solution) strength measuremen

(vol%)

0.75 5ml or 7.5ml 5

1.50 5ml or 7.5ml 5

2.25 2.5ml or 5ml 5

3.00 2.5ml or 5ml 5

Preparing the solution

The extracted fiber powder was weighed on an electronic weight (Sartorius Analytic A2005, Germany) to the nearest third decimal (mg) . Demineralized water (Milli-Q Plus) was measured in 100ml glass beaker. Mixing took place in 100ml disposable plastic cup on the magnetic stirring (KM02 Basic IKA-Werke) with 500 rpm for 5 min and then placed in water bath (37°c) allowing the fibers to fully hydrate of approximately 90-120 min. duration.

After preparation of all fiber solutions we added either 2.5ml - 5 ml - 7.5ml of calcium carbonate solution (CaC0₃ 0.5 mol/1 = 5ml/ 100ml) (Sigma-Aldrich Denmark A/S), which is equivalent to approx. 500 mg of calcium per liter fiber solution.

Gel formation

Of the prepared fiber solution 100ml was taken into plastic beaker and placed on magnetic stirrer with stirring (600-800 rpm) . For control of pH a pH meter (Metrohm Swiss model 691) was used in the solution. Then we added 2 ml of 0.2 mol of HC1 (hydrochloric acid) (total HC1 volume of 20 ml) every 10 seconds until the pH value was between 1.5 - 2.0. Gel strength

In non-newtonic material as our gel mass, the viscosity will not be constant. Therefore, oscillatoric shear rheology was used to examine the gels ability to withstand a given mechanical stress.

Thereby, we could characterize the elastic gel network (= strength) . The oscillatoric shear rheology was performed on a Bohlin C-Vor rheometer (Malvern Instruments Ltd. UK) at constant shear rate (lHz) . The actual stress amplitude varied more than 25 steps, where the mechanical stress was controlled and gradually increased from 1-500 (Pa = lg x cm-1 x s-1) . Stress was applied for 12 sec. one time for each step and voltage amplitude was recorded, and the elastic (G') and viscous (G'') modulus calculated. During oscillations measurements there were obtained a plateau in the elastic modulus. To achieve a single value for the gel mass strength, we have reported the mean of the elastic modulus in this report .

Data analysis

Examination of gel the measurements of oscillation were repeated five times. Results are expressed as means. Difference in gel strength has been compared visually.

Results

Figure 10 shows the measurement of gel strength (elastic modul, Pas) recorded by oscillatory shear rheology and as evident from said figure the inventors observed a clear concentration- response curve as the gel strength increased with higher alginate concentrations. Elastic modulus increased with increased alginate concentration. By visually comparison the two highest concentration of Manugel DMB (2.25% and 3%) we observed a larger gel strength (-3500 Pa and -5100 Pa, respectively) . The experiments conducted using Manugel LBA and Protanal LFR 5/60, showed gel strengths around -2100 Pa for Manugel LBA (-2100 Pa) and around -2200 Pa for Protanal LFR 5/60.

As is evident from fig. 11 the gel strength (elastic modul, Pas) increased with higher calcium content of the low Manugel DMB solutions (0.75% + 1.5%) . Furthermore it seems as the high Manugel DMB concentrations does not reach their peak gel strength when only 2.5ml calcium have been added. When manipulating the added calcium content, the inventors observed that the Manugel DMB solutions with the lowest concentration (0.75% and 1.5%) exhibited higher gel strength when addition of calcium increased from 5ml to 7.5ml. Similar were addition of a smaller amount of calcium (from 5ml to 2.5ml) to the Manugel DMB solutions of 2.25% and 3%, causing a decrease in the gel strength. Corresponding findings when modulating the calcium addition have been observed in lab tests with Protanal LFR 5/60, which reinforce the importance of calcium ions effects on gelling abilities.

It is noteworthy that the Manugel® DMB solution with 1.5% concentration increased the gel strength from - 1500 to -3000 Pa when calcium content was increased. This high gel strength was similar to the 2.25% concentration with 2.5ml and 5 ml calcium. This indicates that a lower Manugel® DMB concentration is possible for achieving acceptable gel strength as long as the calcium content is well monitored, making Manugel® DMB a desirable component in the solid oral formulation according to the invention.

Claims

Claims

A solid oral formulation for the treatment or prevention of overweight or obesity and/or for stabilizing the blood sugar levels in an individual, said formulation comprises an alginate, at least one multivalent cation source and at least one disintegrating agent, and wherein the amount of alginate in the solid oral formulation is sufficient for a gel to be formed having a gel strength of 1000 Pa or more when dissolved in an aqueous liquid at simulated gastric conditions of pH 3.

A solid oral formulation according to claim 1, wherein the disintegrating agent is one or more agents selected from the group comprising,

a wicking agent, preferably selected from the group of colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, alumina, niacinamide, sodium lauryl sulfate, low molecular weight polyvinyl pyrrolidone, m-pyrol, bentonite, magnesium aluminum silicate, polyester, polyethylene, and microcrystalline cellulose,

a swelling agent preferably selected from the group of pregelatinized starch or any type of modified starch, and sodium carboxy methylcellulose, and/or an alkaline salt, such as NaHC0₃, Na₂C0₃, KHC0₃, K₂C0₃, and any combinations thereof.

A solid oral formulation according to claim 1 or 2, wherein the gel strength is 2000 Pa or more, preferably 4000 Pa or more or even more preferably 8000 Pa or more.

A solid oral formulation according to any of the claims 1 - 3, wherein the gel weight obtained at simulated gastric conditions of pH 3, is above 80 g/100 ml water, more preferably above 93 g/100 ml, more preferably above 95 g/100 ml water.

A solid oral formulation according to any of the preceding claims, wherein the gel at simulated gastric conditions of pH 3 has a volume between 400 ml and 600 ml, preferably about 500 ml .

A solid oral formulation according to any of the preceding claims, wherein the at least one multivalent cation source is a salt comprising a cross-linking polyvalent metal ion, said salt is preferably selected from of the group consisting of calcium phosphate, calcium carbonate, calcium sulfate, calcium oxide, calcium citrate, calcium chloride, and calcium lactate.

A solid oral formulation according to any of the preceding claims, wherein the multivalent cation source has a solubility of at least 5 mg per ml at 20°C and pH 7.

A solid oral formulation according to any of the preceding claims, wherein the oral formulation further comprises at least one suspending agent and/or at least one HM pectin and/or at least one carrier.

A solid oral formulation according to claim 8, wherein the suspending agent is selected from the group consisting of inulin, polydextrose , dextrin, oligofructose or combination of these.

A solid oral formulation according to claim 8 or 9, wherein the ratio of the alginate to the suspending agent in the formulation preferably is about 1:1 to 20:1, more preferably 5:1 to 10:1.

A solid oral formulation according to any of the preceding claims, wherein the alginate is a Manugel⁸ DMB .

12. A solid oral formulation according to any of the preceding claims, wherein the alginate is a combination of alginates, preferably a composition comprises at least one low viscosity alginate having a viscosity of less than about 100 mPaS in a 1 wt% aqueous solution and at least one high viscosity alginate having a viscosity of more than about 100 mPaS in a 1 wt% aqueous solution.

A solid oral formulation according to any of the preceding claims, wherein the solid oral formulation is in the form of a shell/core capsule, preferably in the form of a unit dosage .

A solid oral formulation according to claim 13, wherein said unit dosage comprises at least 500 mg alginate, preferably at least 800 mg and even more preferably at least 1200 mg.

A method for non-therapeutic treatment or prevention of overweight /obesity and/or for stabilizing blood sugar levels in an individual comprising the step of administering at least one solid oral formulation according to any of the claims 1 - 14, together with an aqueous liquid of 350 ml or more, preferably at least 500 ml.

A method according to claim 15, wherein the of oral formulation comprises at least 3 g alginate, more preferably at least 5 g alginate and even more preferably at least 7.5 g alginate.

A method according to claim 15 or 16, wherein the aqueous liquid is consumed within 30 minutes or less measured from the administration of the solid oral formulation.

18. A method according to any of the claims 15 - 17, wherein the solid oral formulation is dissolved in the stomach in less than 15 min.

19. Use of the solid oral formulation according to any of the claims 1 - 14 for the treatment or prevention of overweight or obesity in therapy and/or for the cosmetic treatment of prevention of overweight.

20. Use of the solid oral formulation according to any of the claims 1 - 14 for stabilizing blood sugar levels in an individual .